B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in the Western world with as many as 10,000 new cases reported each year in the United States (Rai, K. & Patel, D. C. (1995) in Hematology: Basic Principles and Practice, eds. Hoffman et al. (Churchill Livingstone, New York), pp. 1308-1321; Landis, S. H., Murray, T., Bolden, S. & Wingo, P. A. (1998) CA cancer J. Clin. 48, 6-29). Characteristically B-CLL is a disease of elderly people resulting from the progressive accumulation of a leukemic clone that may be derived from a normal CD5+ B lymphocyte (Caligaris-Cappio, F., Gobbi, M., Bofill, M. & Janossy, G. (1982) J. Exp. Med. 155, 623-628). B-CLL has a consistent association with CD5 expression (Caligaris-Cappio, F., Gobbi, M., Bofill, M. & Janossy, G. (1982) J. Exp. Med. 155, 623-628) and while there is still a debate on the role and significance of CD5 expression on B cells, it remains reasonable to consider CD5+ B cells as the normal counterpart of B-CLL (Boumsell, L., Bernard, A.; Lepage, V., Degos, L., Lemerle, J. & Dausset, J., L. (1978) Eur. J. Immunol. 8, 900-904; Kantor, A. B. (1991) Immunol. Today 12, 389-391).
Human hematopoietic malignancies are often caused by chromosome translocations involving either T-cell receptor (TCR) or Immunoglobulin (Ig) loci (Croce, C. M. (1987) Cell 49, 155-156). These chromosome breakpoints juxtapose enhancer elements of TCR and Ig loci to proto-oncogenes, leading to tumor initiation through oncogene deregulation (Dalla-Favera, R., Bregni, M., Erikson, J., Patterson, D., Gallo, R. C. & Croce, C. M. (1982) Proc. Natl. Acad. Sci. USA 79, 7824-7827; ar-Rushdi, A., Nishikura, K., Erikson, R. W., Rovera, G. & Croce C. M. (1983) Science 222, 390-393).
The TCL1 gene, which has been identified at chromosome 14q32.1 (Virgilio, L., Narducci, M. G., Isobe, M., Billips, L. G., Cooper, M. D., Croce, C. M. & Russo, G. (1994) Proc. Natl. Acad. Sci. USA 91, 12530-12534), is commonly activated by inversions or translocations that juxtapose it to a T cell receptor locus at 14q11 or 7q35. The TCL1 gene is involved in chromosomal translocations and inversions in mature T-cell leukemias. These leukemias are classified either as T prolymphocytic leukemias, which occur very late in life, or as T chronic lymphocytic leukemias, which often arise in patients with ataxia telengiectasia (AT) at a young age. TCL1 has been found to be over expressed in sporadic and ataxia telangiectasia associated T-PLL (Narducci, M. G., Stoppacciaro A., Imada, K., Uchiyama, T., Virgilio, L., Lazzeri, C., Croce, C. M. & Russo G. (1997) Cancer Res. 57, 5452-5456; Thick, J., Metacalfe, J. A., Mak, Y-F., Beatty, D., Minegishi, Dyer, M. J. S., Lucas, G. & Taylor, A. M. R. (1996) Oncogene 12, 379-386). In transgenic animals the deregulated expression of TCL1 leads to mature T-cell leukemia, demonstrating the role of TCL1 in the initiation of malignant transformation in T-cell neoplasia. Evidence has been provided that TCL1 is a bona fide oncogene; a transgenic mouse model has been developed in which ectopic expression driven by the lck promoter in the T-cell compartment results in the development of mature T-cell leukemias after a long latency period, in a pattern closely resembling human mature T-cell leukemia (Virgilio, L., Lazzeri, C., Bichi, R., Nibu, K., Narducci, M. G., Russo G., Rothstein, J. L. & Croce C. M. (1998) Proc. Natl. Acad. Sci. USA 95, 3885-3889). In normal T-cells, TCL1 is only expressed at the very early CD4−/CD8− double negative stage, whereas more mature T-cells lack TCL1 expression (Virgilio, L., Narducci, M. G., Isobe, M., Billips, L. G., Cooper, M. D., Croce, C. M. & Russo, G. (1994) Proc. Natl. Acad. Sci. USA 91, 12530-12534). In the B-cell lineage, the product of the TCL1 gene, Tcl1, has been found in pre-B-cells, surface IgM expressing virgin B-cells, mantle cells and germinal center B-cells, whereas it is down-regulated at later stages of B-cell differentiation, i.e. plasma cells (Virgilio, L., Narducci, M. G., Isobe, M., Billips, L. G., Cooper, M. D., Croce, C. M. & Russo, G. (1994) Proc. Natl. Acad. Sci. USA 91, 12530-12534). Interestingly, high levels of Tcl1 have been found in a broad variety of human tumor-derived B-cell lines ranging from pre-B cell to mature B cell and in many cases of B-cell neoplasias (Takizawa, J., Suzuki, R., Kuroda, H., Utsunomiya, A., Kagami, Y., Joh, T., Aizawa, Y., Ueda, R. & Seto, M. (1998) Jpn. J. Cancer Res. 89, 712-718; Narducci, M. G., Pescarmona, E., Lazzeri, C., Signoretti, S., Lavinia, A. M., Remotti, D., Scala, E., Baroni, C. D., Stoppacciaro, A., Croce, C. M., et al. (2000) Cancer Res. 60, 2095-2100). To further elucidate the role of TCL1 in B cell development and in B cell neoplasia, the present inventor generated transgenic mice under the control of a promoter and enhancer whose activity specifically targets expression of the transgene to the B-cell compartment (Shaw, A. C., Swat, W., Ferrini, R., Davidson, L. & Alt, F. W. (1999) J. Exp. Med. 189, 123-129). It is demonstrated herein that Eμ-TCL1 transgenic mice develop a disease resembling human CLL. The mice develop at first a preleukemic state evident in blood, spleen, bone marrow, peritoneal cavity and peripheral lymphoid tissue, developing later a frank leukemia with all the characteristics of CLL. These findings strongly indicate that TCL1 and/or other gene(s) in the TCL1 pathway are responsible for the initiation of human CLL. The animal model described herein thus provides an in vivo model for human B-CLL.